In very general terms, a virus is an infectious agent made up of nucleic acid and protein that is inert outside a host cell. Upon infection, the virus causes a change in the nucleic acid and protein metabolism of the host cell. As a result, some or all of the viral genes are transcribed and/or translated, sometimes killing the host cell. A mature virus is termed a "virion" and consists of a shell of protein units arranged around a central core of nucleic acid. Viruses exist in a variety of forms, including icosahedral viruses having their envelope protein subunits arranged in the form of a polyhedron of 20 triangular faces, viruses having a cylindrical form, and viruses having a DNA-containing head and a long tail such as a bacteriophage. Viruses are divided into those that infect vertebrate animals, angiosperms, arthopods or bacteria. Only the bacteriophage possess an apparatus for injection of the nucleic acid into the host cell; other viruses are taken up intact by the host cell.
A representative example of an envelope icosahedral virus is cytomeglovirus (CMV), human (HCMV) or murine (MCMV), which contains a core of double-stranded DNA. More specifically, HCMV is a ubiquitous member of the herpes virus family that can induce a wide range of diseases, typically in newborns and immunocompromised adults. Nearly one percent of all live births in the United States are associated with congenital HCMV infection, with approximately 5 to 10 percent of infections resulting in significant neurological defects. In bone marrow transplant recipients, mortality due to HCMV pneumonia can be as high as forty percent. In addition, disseminated HCMV infection is common in immunocompromised patients, such as AIDS patients, and is frequently associated with conditions such as gastroenteritis and sight-threatening chorioretinitis.
In addition to CMV (also referred to as HHV-5), other types of herpes viruses have been described, including: herpes simplex virus (HSV-1) which can account for oral lesions such as fever blisters; human herpes virus (HHV-2) which is a sexually transmitted disease and produces lesions below the waistline, including veneral disease of the vagina and vulva, as well as herpetic ulcers of the penis; herpes varicella-zoster (HHV-3) which occurs clinically as either an acute form known as chickenpox or a chronic form termed shingles; Epstein-Barr virus (HHV-4) which has been linked to aplastic anemia, chronic fatigue syndrome, Burkitt's lymphoma, histiocytic sarcoma, hairy cell leukemia and immunocompromised patients; human B cell lymphotrophic virus (HHV-6) which is responsible for exanthem subitum; and HHV-7, a T cell lymphotrophic virus.
In order to successfully treat viral infection, particularly viral infection by viruses of the herpes family, there is a need for new agents that inhibit viral gene expression, as well as a need for methods of treating conditions associated with such infections. The present invention fulfills these needs and provides further related advantages.